Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.
Adipocytes
/ drug effects
Adipose Tissue
/ drug effects
Aged
Biomarkers
Biopsy
Cellular Senescence
/ drug effects
Clinical Trials, Phase I as Topic
Dasatinib
/ pharmacology
Diabetic Nephropathies
/ diagnosis
Drug Therapy, Combination
Female
Humans
Immunohistochemistry
Kidney Function Tests
Macrophages
/ drug effects
Male
Middle Aged
Quercetin
/ pharmacology
Cellular senescence
Dasatinib
Diabetic kidney disease
Quercetin
Senescence-associated secretory phenotype
Senolytics
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
31
07
2019
revised:
16
08
2019
accepted:
29
08
2019
pubmed:
23
9
2019
medline:
31
1
2020
entrez:
23
9
2019
Statut:
ppublish
Résumé
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16 "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Sections du résumé
BACKGROUND
BACKGROUND
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.
METHODS
METHODS
In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m
FINDINGS
RESULTS
D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16
INTERPRETATION
CONCLUSIONS
"Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Identifiants
pubmed: 31542391
pii: S2352-3964(19)30591-2
doi: 10.1016/j.ebiom.2019.08.069
pmc: PMC6796530
pii:
doi:
Substances chimiques
Biomarkers
0
Quercetin
9IKM0I5T1E
Dasatinib
RBZ1571X5H
Banques de données
ClinicalTrials.gov
['NCT02848131']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
446-456Subventions
Organisme : NIDDK NIH HHS
ID : K23 DK109134
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK118120
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H022384/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R37 AG013925
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG062413
Pays : United States
Organisme : NIA NIH HHS
ID : R33 AG061456
Pays : United States
Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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